Abstract
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.
Highlights
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives
The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation
The compounds were synthesized via condensation of amino steroids with arylaldehydes, and subsequent NaBH4reduction of obtained Schiff-bases furnished the desired compounds in high yields
Summary
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. Despite its simple substitution patterns, it was reported to exhibit activity against the malaria parasite Plasmodium falciparum[9], and a series of amino steroids having side chains similar to that of sarachine were prepared from deoxycholic acid as the starting material[10] To this end, the most active derivative of this series contained a chloroquinoline moiety in the side chain, which might be contributing to biological activity. The compounds are active in vitro against human and murine Plasmodium asexual blood stages as well as against P. falciparum gametocytes They exhibit in vivo activity in Plasmodium berghei-infected mice and block the transmission of parasites to mosquitoes. The lipophilic steroid carrier of these antiparasitic lead compounds is likely to facilitate membrane permeation and bioavailability whereas the essential hydroxyarylmethylamino moiety points to a chelate-based quinone methide mechanism involving metal or haem bioactivation
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